Intensity-Modulated Radiation Therapy, Etoposide, and Cyclophosphamide Followed By Donor Stem Cell Transplant in Treating Patients With Relapsed or Refractory Acute Lymphoblastic Leukemia or Acute Myeloid Leukemia

Phase I-II Study of Escalating Doses of Large Field Image-Guided Intensity Modulated Radiation Therapy (IMRT) Using Helical Tomotherapy in Combination With Etoposide (VP16) and Cytoxan as a Preparative Regimen for Allogeneic Hematopoietic Stem Cell (HSC) Transplantation for Patients With Poor Risk Acute Lymphocytic Leukemia (ALL) or Poor Risk Acute Myelogenous Leukemia (AML)

RATIONALE: Giving intensity modulated radiation therapy (IMRT) and chemotherapy, such as etoposide and cyclophosphamide, before a donor stem cell transplant helps stop the growth of cancer cells. It also helps stop the patient's immune system from rejecting the donor's stem cells. When the healthy stem cells from a donor are infused into the patient they may help the patient's bone marrow make stem cells, red blood cells, white blood cells, and platelets. Sometimes the transplanted cells from a donor can make an immune response against the body's normal cells. Giving IMRT together with chemotherapy before transplant may stop this from happening.

PURPOSE: This phase I/II trial is studying the side effects and best dose of intensity-modulated radiation therapy (IMRT) when given together with etoposide and cyclophosphamide followed by donor stem cell transplant and to see how well they work in treating patients with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloid leukemia (AML).

Study Overview

• Status: Active, not recruiting
• Conditions: Leukemia
• Intervention / Treatment: Drug: cyclophosphamide; Drug: etoposide; Procedure: allogeneic bone marrow transplantation; Procedure: allogeneic hematopoietic stem cell transplantation; Procedure: peripheral blood stem cell transplantation; Radiation: intensity-modulated radiation therapy; Radiation: tomotherapy

Detailed Description

OBJECTIVES: I. To establish the maximum tolerated dose [MTD] of large field image-guided IMRT, using helical tomotherapy when given in combination with intravenous cyclophosphamide and VP-16 as a preparative regimen for allogeneic hematopoietic stem cell transplantation (HSCT) from an human leukocyte antigen (HLA)-identical sibling or unrelated donor in patients with ALL or AML with induction failure or in relapse. (Phase I) II. To describe the toxicity at each dose level standard. (Phase I) III. To collect data on the radiation dose to normal organs and bone marrow using tomotherapy targeted total-body irradiation (TBI). (Phase I) IV. To estimate the overall survival probability, disease free survival probability and relapse rate associated with this regimen. (Phase II) V. To characterize the treatment related mortality and toxicity profile (early/late) associated with this regimen. (Phase II) VI. To descriptively compare the outcomes of patients treated on this protocol to a comparable patient population conditioned with whole body radiation. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of intensity-modulated radiation therapy (IMRT) followed by a phase II study.

PREPARATIVE REGIMEN: Patients undergo IMRT using helical tomotherapy once or twice daily on days -10 to -6 or -10 to -7. Patients also receive etoposide intravenously (IV) on day -6 or -5 and cyclophosphamide IV on day -4 or -3.

TRANSPLANTATION: Patients undergo allogeneic peripheral blood stem cell or bone marrow transplantation on day -1 or day 0. After completion of study treatment, patients are followed up periodically for up to 2 years.

• Study Type: Interventional
• Enrollment (Actual): 51
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010-3000
      • City of Hope Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 7 years to 55 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with acute lymphocytic leukemia or acute myelogenous leukemia who are not in first or second remission (i.e., after failing remission induction therapy or in relapse or beyond second remission)
• All candidates for this study must have a human leukocyte antigen (HLA) (A, B, C, DR) identical sibling who is willing to donate bone marrow or primed blood stem cells or a 10/10 allele matched unrelated donor; a single allele mismatch at A, B, C, DR, or DQ and a KIR mismatch at C will be allowed; all ABO blood group combinations of the donor/recipient are acceptable since even major ABO compatibilities can be dealt with by various techniques
• Prior therapy with VP-16, Busulfan, and Cytoxan is allowed
• A cardiac evaluation with an electrocardiogram showing no ischemic changes or abnormal rhythm and an ejection fraction of >= 50% established by multi gated acquisition scan (MUGA) or echocardiogram
• Patients must have a serum creatinine of less than or equal to 1.2 or creatinine clearance > 80 ml/min
• A bilirubin of less than or equal to 1.5
• Serum glutamic oxaloacetic transaminase (SGOT) less than 5 times the upper limit of normal
• Serum glutamate pyruvate transaminase (SGPT) less than 5 times the upper limit of normal
• Pulmonary functioning tests including diffusing capacity of carbon monoxide (DLCO) will be performed; forced expiratory volume in one second (FEV1) and DLCO should be greater than 50% of the predicted normal value
• The time from the end last induction or reinduction attempt should be >= 14 days
• Signed informed consent form approved by the Institutional Review Board (IRB) is required

DONOR: Any sibling donors who are histocompatible with the prospective recipient will be considered a suitable donor

• Donors will be excluded if for psychological or medical reasons they are unable to tolerate the procedure
• Donor should be able to donate peripheral blood stem cells or bone marrow

Exclusion Criteria:

• Prior radiation therapy that would exclude the use of total-body irradiation
• Patients who have undergone bone marrow transplantation previously and who have relapsed
• Patients with psychological or medical condition that patients physician deems unacceptable to proceed to allogeneic bone marrow transplant
• Pregnancy
• Electrocardiogram (EKG) showing ischemic changes or abnormal rhythm and/or an echocardiogram or MUGA scan showing abnormal wall motion or ejection fraction < 50%

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Level 1: 1200cGy; 150cGy BID x Days 1-4. Total dose 1200cGy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 2: 1350cGy; 150cGy BID Day 1-4 then 150 cGy QD Day 5. Total dose 1350cGy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 3: 1500cGy limited dose to ribs, sternum, liver, brain 1200cGy; 150cGy BID Day 1-5. Total dose 1500Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 4: 1500cGy limited dose to liver, brain 1200cGy; 150cGy BID Day 1-5. Total dose 1500Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 5: 1600cGy limited dose to liver, porta-hepatic, brain 1200cGy; 160cGy BID Day 1-5. Total dose 1600Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 6: 1700cGy limited dose to liver, porta-hepatic, brain 1200cGy; 170cGy BID Day 1-5. Total dose 1700Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 7: 1800cGy limited dose to liver, porta-hepatic, brain 1200cGy; 180cGy BID Day 1-5. Total dose 1800Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 8: 1900cGy limited dose to liver, porta-hepatic, brain 1200cGy; 190cGy BID Day 1-5. Total dose 1900Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy
Experimental: Level 9: 2000cGy limited dose to liver, porta-hepatic, brain 1200cGy; 200cGy BID Day 1-5. Total dose 2000Gy.	Drug: cyclophosphamide; Given IV; Other Names: Cytoxan; Endoxan; CPM; CTX; Endoxana; Drug: etoposide; Given IV; Other Names: EPEG; VP-16; VP-16-213; Procedure: allogeneic bone marrow transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: allogeneic hematopoietic stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Procedure: peripheral blood stem cell transplantation; Occurs approximately 48 hours after completion of cyclophosphamide; Radiation: intensity-modulated radiation therapy; Undergo IMRT; Other Names: IMRT; Radiation: tomotherapy; Undergo IMRT using helical tomotherapy; Other Names: helical tomotherapy

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Tolerated Dose of Intensity-modulated Radiotherapy (Phase I)	Toxicities will be recorded using two distinct grading systems: the modified Bearman scale and the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 3.0 scale.	30 days post transplant

Secondary Outcome Measures

Outcome Measure	Time Frame
Infection (Phase II)	2 years post transplant
Acute and chronic graft-versus-host disease (Phase II)	2 years post transplant

Collaborators and Investigators

• Sponsor: City of Hope Medical Center
• Collaborators: National Cancer Institute (NCI)
• Investigators: Study Chair: Anthony S. Stein, MD, City of Hope Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 4, 2008
• Primary Completion (Actual): May 30, 2016
• Study Completion (Estimated): December 30, 2024

Study Registration Dates

• First Submitted: December 18, 2007
• First Submitted That Met QC Criteria: December 18, 2007
• First Posted (Estimated): December 19, 2007

Study Record Updates

• Last Update Posted (Actual): April 2, 2024
• Last Update Submitted That Met QC Criteria: March 29, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: recurrent adult acute lymphoblastic leukemia; recurrent childhood acute lymphoblastic leukemia
• Additional Relevant MeSH Terms: Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Hematologic Diseases; Leukemia, Lymphoid; Leukemia; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Phytogenic; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Cyclophosphamide; Etoposide; Etoposide phosphate
• Other Study ID Numbers: 05021; CHNMC-05021; CDR0000579141 (Registry Identifier: NCI PDQ); NCI-2010-00427 (Registry Identifier: NCI CTRP); R01CA154491 (U.S. NIH Grant/Contract)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No